The blood brain barrier is a term used for the unique structure and properties of the capillary network of the central nervous system which makes the interface which allows entry of selective substances to the brain whereas holds or blocks others. Thus it is a kind of check that permits some of the circulating things to cross to the brain but puts a stop on the others.
These restrictions help to tightly regulate brain homeostasis. This not only allows proper neuronal functioning but also protects the brain from toxins, pathogens, inflammation, injury, and disease.
The actual term for this barrier is the Blood-CNS barrier as this property is not found only in brain microvessels but also in those of the spine. The latter is also called the blood-spinal cord barrier.
Just mentioned similar barriers of different restrictive abilities also exist in the eye, thymus, testicles, etc.
There are several parts of the brain that do not have a tight blood-brain barrier. These include the circumventricular organs, the roof of the third and fourth ventricles and the pineal gland.
Thus, melatonin secreted by the pineal gland is released into circulation and is not subjected or affected by blood brain barrier.
The blood brain barrier functions to protect the brain from exposure to harmful substances like toxins or infectious agents.
However, the same blood brain barrier also becomes an obstacle to deliver something to the brain, for example, drugs.
Blood brain barrier dysfunction is part of many neuronal conditions too.
Structure of Blood Brain Barrier
The blood brain barrier [the microvessels] consists of two main cell types
- Endothelial cells that form the wall of the blood vessels [Luminal cells]
- Mural cells on the abluminal side [Abluminal cells]
Abluminal side means side not facing the luminal side. In this context the abluminal side is the brain side.
The features of blood brain barrier are mostly manifested by endothelial cells but are regulated by mural cells, immune cells, glial cells, and neural cells interacting with the neurovascular units.
Endothelial cells form the lumen of the vessels. Central nervous system endothelial cells are unique as they are held together by tight junctions which limit the flow of solutes.
This creates a tight paracellular barrier. Along with the transcellular barrier, this creates a polarized cell with distinct luminal and abluminal membrane compartments to regulate the transport of substances.
Mural cells are vascular smooth muscle cells surrounding the vessels and pericytes.
Pericytes sit on the abluminal surface of the endothelial tube [formed by endothelial cells] and are embedded in the vascular basement membrane.
Central nervous system pericytes are unique since they are derived from the neural crest as compared to pericytes in the peripheral tissues which are derived from mesoderm.
Pericytes have a role in the regulation of
- Formation of new vessels [angiogenesis]
- Deposition of extracellular matrix
- Wound healing
- Immune cell infiltration
- Blood flow in response to neural activity
There are two basement membranes
- Inner or vascular
- An extracellular matrix secreted by the endothelial cells or pericytes
- Outer or the parenchymal
- Secreted by astrocytic processes that extend towards vessels
Basement membranes provide an anchor for many signaling processes and an additional barrier for molecules and cells to cross before accessing the neural tissue
Astrocytes are glial cells or supportive cells between neurons. These extend cellular processes that ensheath either neuronal processes or blood vessels.
Astrocytes are now recognized as important mediators that modulate and maintain the barrier once it is formed.
The central nervous system interacts with different immune cells mainly perivascular macrophages which lie on the abluminal side and microglial cells.
These cells are derived from blood-borne progenitor cells and are able to cross blood brain barrier.
Molecules involved in regulation and function of blood brain barrier
Blood-brain barrier is regulated by complex cellular signaling mechanisms. While complete molecular events are beyond the scope of this article, the important molecules are mentioned below.
- Transmembrane molecules
- Junctional adhesion molecules
- Efflux transporters
- Breast Cancer Resistance Protein or BCRP
- MDR 1
- Efflux transporters
- Nutrient transporters
- Transcytosis [Transport through cells]
- Leukocyte Adhesion Molecules for immune surveillance
Function of Blood Brain Barrier
The blood-brain barrier is a protective mechanism of the brain. A kind of boundary where selected things are allowed to pass.
It protects against the brain against the infection as it filters out circulating pathogens. The blood borne infections of the brain are rare.
But the barrier can act as double-edged sword too. Due to the barrier, infections of the brain are difficult to treat as antibodies are not able to cross the barrier. Moreover, only certain antibiotics are able to cross the barrier making it necessary to administer them through other routes such as via cerebrospinal fluid.
Dysfunctional Blood Brain Barrier
The blood brain barrier may not function well in certain conditions like amyotrophic lateral sclerosis, epilepsy, brain trauma and edema and could be an important factor in pathophysiology in certain other diseases. Examples include multiple sclerosis, neuromyelitis optica, Alzheimer’s disease, HIV encephalitis and neuromyelitis optica.
It also may be breached in systemic diseases like liver failure.
Therapeutic Drugs and Blood Brain Barrier
Because the blood brain barrier is quite selective, it allows a few drugs to cross it.
The methods for targeted delivery that are being worked are using osmotic means or vasoactive substances, using vectors targeting blood brain barrier transporters such as transferrin, intracerebral implantation (bypasses the blood brain barrier) and using nanotechnology.
- Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, et al. 2010. Pericytes regulate the blood-brain barrier. Nature 468: 557–561.
- Zlokovic BV 2008. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57: 178–201.